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==Structure of Human Enolase 2 in complex with SF2312== | ==Structure of Human Enolase 2 in complex with SF2312== | ||
<StructureSection load='4zcw' size='340' side='right' caption='[[4zcw]], [[Resolution|resolution]] 1.99Å' scene=''> | <StructureSection load='4zcw' size='340' side='right'caption='[[4zcw]], [[Resolution|resolution]] 1.99Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[4zcw]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4ZCW OCA]. For a <b>guided tour on the structure components</b> use [ | <table><tr><td colspan='2'>[[4zcw]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4ZCW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4ZCW FirstGlance]. <br> | ||
</td></tr><tr id=' | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.992Å</td></tr> | ||
<tr id=' | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=4NG:[(3S,5S)-1,5-DIHYDROXY-2-OXOPYRROLIDIN-3-YL]PHOSPHONIC+ACID'>4NG</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr> | ||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4zcw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4zcw OCA], [https://pdbe.org/4zcw PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4zcw RCSB], [https://www.ebi.ac.uk/pdbsum/4zcw PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4zcw ProSAT]</span></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | |||
</table> | </table> | ||
== Function == | == Function == | ||
[ | [https://www.uniprot.org/uniprot/ENOG_HUMAN ENOG_HUMAN] Has neurotrophic and neuroprotective properties on a broad spectrum of central nervous system (CNS) neurons. Binds, in a calcium-dependent manner, to cultured neocortical neurons and promotes cell survival (By similarity). | ||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Despite being crucial for energy generation in most forms of life, few if any microbial antibiotics specifically inhibit glycolysis. To develop a specific inhibitor of the glycolytic enzyme enolase 2 (ENO2) for the treatment of cancers with deletion of ENO1 (encoding enolase 1), we modeled the synthetic tool compound inhibitor phosphonoacetohydroxamate (PhAH) into the active site of human ENO2. A ring-stabilized analog of PhAH, in which the hydroxamic nitrogen is linked to Calpha by an ethylene bridge, was predicted to increase binding affinity by stabilizing the inhibitor in a bound conformation. Unexpectedly, a structure-based search revealed that our hypothesized backbone-stabilized PhAH bears strong similarity to SF2312, a phosphonate antibiotic of unknown mode of action produced by the actinomycete Micromonospora, which is active under anaerobic conditions. Here, we present multiple lines of evidence, including a novel X-ray structure, that SF2312 is a highly potent, low-nanomolar inhibitor of enolase. | |||
SF2312 is a natural phosphonate inhibitor of enolase.,Leonard PG, Satani N, Maxwell D, Lin YH, Hammoudi N, Peng Z, Pisaneschi F, Link TM, Lee GR 4th, Sun D, Prasad BA, Di Francesco ME, Czako B, Asara JM, Wang YA, Bornmann W, DePinho RA, Muller FL Nat Chem Biol. 2016 Oct 10. doi: 10.1038/nchembio.2195. PMID:27723749<ref>PMID:27723749</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 4zcw" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Enolase 3D structures|Enolase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: | [[Category: Homo sapiens]] | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: | [[Category: Czako B]] | ||
[[Category: | [[Category: Leonard PG]] | ||
[[Category: | [[Category: Maxwell D]] | ||
[[Category: | [[Category: Muller FL]] | ||
Latest revision as of 11:16, 27 September 2023
Structure of Human Enolase 2 in complex with SF2312Structure of Human Enolase 2 in complex with SF2312
Structural highlights
FunctionENOG_HUMAN Has neurotrophic and neuroprotective properties on a broad spectrum of central nervous system (CNS) neurons. Binds, in a calcium-dependent manner, to cultured neocortical neurons and promotes cell survival (By similarity). Publication Abstract from PubMedDespite being crucial for energy generation in most forms of life, few if any microbial antibiotics specifically inhibit glycolysis. To develop a specific inhibitor of the glycolytic enzyme enolase 2 (ENO2) for the treatment of cancers with deletion of ENO1 (encoding enolase 1), we modeled the synthetic tool compound inhibitor phosphonoacetohydroxamate (PhAH) into the active site of human ENO2. A ring-stabilized analog of PhAH, in which the hydroxamic nitrogen is linked to Calpha by an ethylene bridge, was predicted to increase binding affinity by stabilizing the inhibitor in a bound conformation. Unexpectedly, a structure-based search revealed that our hypothesized backbone-stabilized PhAH bears strong similarity to SF2312, a phosphonate antibiotic of unknown mode of action produced by the actinomycete Micromonospora, which is active under anaerobic conditions. Here, we present multiple lines of evidence, including a novel X-ray structure, that SF2312 is a highly potent, low-nanomolar inhibitor of enolase. SF2312 is a natural phosphonate inhibitor of enolase.,Leonard PG, Satani N, Maxwell D, Lin YH, Hammoudi N, Peng Z, Pisaneschi F, Link TM, Lee GR 4th, Sun D, Prasad BA, Di Francesco ME, Czako B, Asara JM, Wang YA, Bornmann W, DePinho RA, Muller FL Nat Chem Biol. 2016 Oct 10. doi: 10.1038/nchembio.2195. PMID:27723749[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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